Project Summary A growing literature has linked air pollution exposures with neurodegenerative outcomes, such as Parkinson's and Alzheimer's Diseases. Air pollution, and specifically urban air pollution, is a ubiquitous exposure that can be modified through public health messages, interventions and regulations. Amyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative disease with no known cure and considerable economic burden. Even though compelling evidence exists, both from toxicological and epidemiologic studies, of a potential link between air pollution and ALS, to date no study has investigated this association. Our goal is to address this significant knowledge gap. Specifically, we will leverage the resources of the Danish National Registers system to identify all ALS diagnosed cases between 1989 and 2013 and match these to age- and sex-matched controls randomly selected from the entire Danish population, who were alive and free of ALS at the date of the case diagnosis. We will then employ state-of-the-art prediction models, with high spatial and temporal resolution, coupled with the life-time residential history of the study participants, to estimate exposure to different air pollutants. We will explore associations with particulate matter (PM) of different sizes (PM ? 10 ?m in aerodynamic diameter, PM10, and ? 2.5 ?m in aerodynamic diameter, PM2.5), which comprise components from multiple different emission sources and secondary formation. We will also focus on a specific air pollution source, traffic, which has been consistently linked to adverse human health. In addition, although it has long been considered that ALS onset generally commences with the recognition of clinical symptoms, recent evidence suggests that earlier exposures might also play an important role. We will, therefore, explore the timing of air pollution exposure and ALS onset, assessing cumulative exposures of different durations, namely 1-, 5-, 10- and 20-years prior to disease diagnosis, as well as lagged exposures. If successful, our study will identify novel and modifiable risk factors for ALS and, by shedding light to the potentially critical exposure windows, help generate hypotheses for other modifiable risk factors as well. Finally, our proposed research can provide new evidence on understanding possible mechanisms of the disease progress.